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The impact of the D614G mutation

SARS-CoV-2 has a genome made up of a single-strand RNA molecule. When it is replicated by the polymerase enzyme to make new virions, copying errors can arise in the sequence. These errors, if they are selectively advantageous, can become dominant. Early in the pandemic, the D614G mutation appeared from the Wuhan strain and quickly became dominant. It endowed the virus with greater infectivity (see the letter, 23-29th November 2020). Researchers in Boston (at the Boston Children’s Hospital, Harvard Medical School, and Harvard Institutes of Medicine) recently analysed modifications in the spike (S) structure brought about by the D614G mutation.

The researchers carried out cryo-microscopy analysis, allowing them to study the S protein’s structure in detail. It was already known to be trimeric (involving the association of three proteins) and its RBD (Receptor Binding Domain) binds with the ACE2 receptor present on cell surfaces. This interaction causes significant changes in the S protein conformation, allowing the fusion of viral and cellular membranes to enable the entry of the virus into the cell. The RBD has two states: an “up” conformation, where the domain is accessible, and a “down” conformation which renders the RBD inaccessible to the ACE2 cellular receptor (see the letter 4-10 January 2021).

Thanks to this latest research, we now know that the D614G mutation does not bring about significant rearrangements in the structure, but seems primarily to have an effect on the stability of the trimeric S protein. In the original D614 strain, the distribution of the RBD “up” and “down” domains is 50-50%. This proportion seems to be increased in favour of the accessible RBD ”up” domain in the G614 variant.

The greater stability of the S protein and the changes in the RBD domain in favour of the accessible conformation of the D614G variant could explain its greater infectivity. Since the S protein is targeted by vaccines, it is important to identify its key mutations and understand their consequences on its structure. All the variants currently in circulation include this mutation.  It will therefore be essential to take it into account as 2nd generation vaccines against COVID-19 are developed.

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